Highly potent and selective inhibitors of casein kinase 1 delta (CK1?) and 1 epsilon (CK1?) were recently identified as a result of high-throughput screening and medicinal chemistry optimization in the Roush laboratory at The Scripps Research Institute Florida. Preliminary studies indicate that this class of purine inhibitors is ideally suited to serve as probes to define the roles of CK1?/CK1? in a host of human cancers. Despite exceptional effectiveness of the current lead compound in animal models, the brain penetration of the lead agent is only 12% which is not suitable for clinical applications for treatment of brain cancer. Although considerable progress has been recently made in the treatment brain tumors, the most effective treatment options remain whole-brain radiation and surgery while medication is mostly palliative or supportive in nature. Iterative medicinal chemistry and DMPK parameters will be used to develop safe, potent, orally bioavailable and brain penetrant CK1?/CK1? inhibitors for treating primary and metastatic brain cancer. Using in-house SAR and DMPK data accompanied with in silico analysis of brain penetration properties, the design of new purine inhibitors for targeted delivery through the blood-brain barrier (BBB) will be accomplished. Firstly, the development of CK1?/? analogs with improved physicochemical properties to enhance passive BBB diffusion will be pursed. Furthermore, the design and synthesis of purine derivatives for active transport by small molecule transporters presented in BBB will be accomplished by chemical modification at C2 and C6 positions by addition of endogenous carrier substrate-like moieties via adjustable linkers. With only a handful compounds approved by the FDA for treatment of brain cancer, completion of the proposed work will provide with a novel series of inhibitors capable of producing a significant impact on the thousands affected by this horrific disease.